Parathyroid hormone (PTH) is the best characterized of the small group of agents that increase bone formation and may become part of a therapy for osteoporosis capable of restoring normal bone mass in this patient group. The actions of parathyroid hormone are mediated by a common receptor for both PTH and PTH-related protein (PTHrP) and involve increases in both bone formation and resorption. The goal of this proposal is to evaluate, in vivo, the roles of PTH and PTH~P in regulating osteoblast and osteoclast development and function by specifically deleting the PTH/PTHrP receptor gene from cells of the osteoblast lineage. The first aim will be to establish lines of mice selectively missing the PTH/PTHrP receptor gene only in osteoblasts of varying degrees of maturity. The cre-lox system will be used to generate mice missing the PTH/PTHrP receptor gene in osteoblasts that express the alpha1(I) collagen gene promoter and in those that express the osteocalcin gene promoter. The second aim will be to assess the role of the PTH/PTHrP receptor in osteoblast development and function. Histomorphometry, BRdU labeling, and in situ hybridization will be used to assess abnormalities of osteoblast development and function. Comparisons of the two types of cre-lox mice will clarify the relative roles of osteoblasts of varying degrees of maturity. Mice missing the PTH gene will be used to assess the individual roles of PTH and PTHrP in activating the PTH/PTHrP receptor to control osteoblast development and function. The third aim will be to assess the role of the PTH/PTHrP receptor in osteoclast development and function. Histomorphometry, urinary markers of bone resorption, and in situ hybridization will be used to assess abnormalities of osteoclast development and function. Comparisons of the two types of cre-lox mice and the use of mice missing the PTH gene will clarify the roles of osteoblasts of differing levels of maturity and the relative roles of PTH and PTHrP. These studies will lead to a better understanding of the potentially conflicting actions of PTH on bone and may lead to more effective use of PTH-like drugs in the treatment of osteoporosis.